The solid-phase method introduced by Merrifield is now firmly established as a powerful technique for the study of biologically important peptides. Synthesis normally begins by covalently liking the C-terminal amino acid residue of the desired peptide to an insoluble polymeric support. This anchoring step is an integral part of the overall synthetic plan, and the experimental details can impact significantly on the overall purity and yield of the final product. As part of our general interest in achieving milder chemical methods for peptide synthesis, we have had several occasions to pursue the advantages of "handle" approaches to anchoring. Handles are defined as bifunctional spacers which serve to attach the initial residue to the polymeric support in two discrete steps. They allow precise control over the stability and ultimate cleavage of the anchoring linkage, and facilitate quantitative attachments which circumvent problems associated with extraneous polymer-bound functional groups. Handles developed in our laboratory are compatible with readily removable N alpha-amino protecting groups such as the highly acid-labile N alpha-biphenylyl- isopropyloxycarbonyl (Bpoc), the base-labile N alpha-9-fluorenylmethyloxycarbonyl (Fmoc), and the thiolysable N alpha-dithiasuccinoyl (Dts) or N alpha-3-nitro-2-pyridine-sulfenyl (Npys) functions. Cleavages of the anchoring linkages occur under relatively mild conditions with acid, light, or fluoride ion; the products may be peptide acids or amides. Application of these handles in orthogonal protection schemes offers the further possibility of preparing partially protected segment suitable for purification followed by restitching to make longer and more complicated products. The present proposal aims to take several handles that have already been worked out in simple systems and demonstrate their scope when applied to challenging peptide targets. Simultaneously, some modified and new chemistries are suggested that may lead to new handles with even better properties and/or a wider range of applications.